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Abstract Number: 950

Identification of Naturally Processed Immunodominant Topoisomerase I Epitopes in Patients with Systemic Sclerosis

Eleni Tiniakou1, Andrea Fava2, Tara Guhr3, Francesco Boin4 and Erika Darrah5, 1Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, 2Johns Hopkins University, Baltimore, MD, 3University of North Carolina, Chapel Hill, NC, 4Rheumatology, University California, San Francisco, San Francisco, CA, 5Department of Medicine/Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, MD

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: dendritic cells and systemic sclerosis, T cells

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Session Information

Date: Sunday, November 5, 2017

Title: T Cell Biology and Targets in Autoimmune Disease

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose:

Identification of immunodominant T cell epitopes of autoantigens is crucial to understanding the pathogenesis of autoimmune diseases and developing disease-specific diagnostic and therapeutic tools. A subset of patients with systemic sclerosis (SSc) exhibit autoantibodies and CD4+ T cells specific for topoisomerase-I (Topo-I), which are quantitatively associated with the presence and severity of lung fibrosis. Mapping of immunodominant Topo-I T cell epitopes has been difficult due to poor sensitivity, high cost of current protocols, and has mainly been based on in silico prediction or overlapping peptide libraries. Existing data are limited by the low precision of these approaches and the poor sensitivity of detection assays. We present a new method for mapping immunodominant Topo-I T cell epitopes using the natural processing and presentation of HLA-DR-restricted Topo-I peptides by monocyte derived dendritic cells (MoDCs) from SSc patients.

Methods:

MoDCs from 6 anti-Topo-I positive SSc patients were pulsed with whole Topo-I protein. Following overnight exposure, immunoprecipitation was performed to isolate HLA-DR/peptide complexes. Peptides were identified by mass spectrometry, and matched to the Topo-I sequence. The peptides were then synthesized and used to stimulate peripheral blood mononuclear cells (PBMCs) from these patients in the presence of anti-CD40 antibody. Topo-I-reactive CD4+ T cells were identified by flow cytometry based on activation status (CD40L/CD154 upregulation). PBMCs from 8 additional randomly selected anti-Topo-I + patients and 6 anti-Topo-I negative controls (anti-centromere or anti-RNA-Polymerase-III) were stimulated using the same protocol.

Results:

Ten different naturally processed Topo-I peptides were identified. The peptides detected were located mainly in the core region of the molecule. The median number of distinct peptides presented by each individual patient was 4 (range 1-8). Peptide overlap among patients existed despite differences in their HLA-DR haplotype, with 8 out of 10 epitopes being presented by two or more subjects. All Topo-I peptides were able to stimulate CD154 upregulation by CD4+ T cells from at least one of the 14 anti-Topo-I positive patients tested. These T cell responses were significantly higher than that of 6 randomly selected anti-Topo-I negative SSc controls (p<0.001).

Conclusion:

Through characterization of naturally processed peptides, we have identified immunodominant Topo-I epitopes capable of stimulating CD4+ T cells from anti-Topo-I positive patients with SSc. Additionally, our approach showed that a restricted set of immunodominant Topo-I epitopes is presented by SSc patients carrying diverse HLA-DR alleles. This method represents a cost-effective and dependable way to identify immunodominant epitopes and can provide novel targets for disease monitoring and eventually, designing peptide-targeted immunotherapy.


Disclosure: E. Tiniakou, None; A. Fava, None; T. Guhr, None; F. Boin, None; E. Darrah, None.

To cite this abstract in AMA style:

Tiniakou E, Fava A, Guhr T, Boin F, Darrah E. Identification of Naturally Processed Immunodominant Topoisomerase I Epitopes in Patients with Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/identification-of-naturally-processed-immunodominant-topoisomerase-i-epitopes-in-patients-with-systemic-sclerosis/. Accessed .
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